Abstract
ABSTRACT
The Thesis entitled “Chemical Investigation on Natural and Synthetic Heterocyclic Compounds” consists of three chapters.
CHAPTER- I
Chemical Investigation on Caesalpinia pulcherrima and Synthesis of Homoisoflavonoids
Chemical Investigation on Caesalpinia pulcherrima PART- A
INRODUCTION
Caesalpinia is a genus of the family Leguminosae. The species belong to this genus are evergreen and deciduous trees, and shrubs grown as an ornamental plant. Various species of Caesalpinia are known for their medicinal properties. The metabolites obtained from different species of Caesalpinia are also chemically interesting. These metabolites are of varied types, viz., different kinds of diterpenoids, flavonoids, homoisoflavonoids and peltogynoids. The constituents of Caesalpinia species are thus both chemically and biologically interesting.
The present investigation relates to the isolation and characterization of four naturally new homoisofalvonoids from Caesalpinia Pulcherrima. These constituents belong to the homoisofalvonoids which are relatively common in nature. The structures of the new molecules have been confirmed by its 1D and 2D NMR (1H-1H COSY, HMQC, HMBC and NOESY), mass spectroscopic studies and comparison with the structurally related compounds in the literature.
The following compounds were isolated from the plant Caesalpinia Pulcherrima.
Table- 1: Compounds isolated from Caesalpinia pulcherrima.
Compound code
/Compound name
/Compound nature
/Remarks
CP-I
/5,7-Dimethoxy-3,4-methylenedioxy flavanone
/Colorless powder
/Known compound
CP-II
/7-Methoxy-3-(3-hydroxy-4-methoxy benzylidene)chroman-4-one
/Light yellow amorphous powder
/Naturally New
CP-III
/7-Methoxy-3-(4-methoxy benzylidene)chroman-4-one
(7-O-methyl bonducellin)
/Light yellow amorphous powder
/Known compound
CP-IV
/7-Methoxy-3-(3,4-methylenedioxy benzylidene)chroman-4-one
/Yellow amorphous powder
/Naturally New
CP-V
/7-Hydroxy-3-(2,4-dimethoxy benzylidene)chroman-4-one (2-methoxy bonducellin)
/Yellow amorphous powder
/Known compound
CP-VI
/7-Hydroxy-3-(3,4-methylenedioxy benzylidene) chroman-4-one
/Yellow solid
/Naturally New
CP-VII
/7-Hydroxy-3-(4-methoxy benzylidene) chroman-4-one (bonducellin)
/Yellow needles
/Known compound
CP-VIII
/7-Methoxy-3-(3-hydroxy-4-methoxy benzylidene)chroman-4-one
/Light yellow amorphous powder
/Naturally New
CP-IX
/7-Hydroxy-3-(3,4-dihydroxy enzylidene)chroman-4-one (sappanone A)
/Yellow solid
/First report
from the speciesCP-X
/ 3,6,7,4,5-Pentamethoxy-5,3-dihydroxyflavone /Yellow solid
/First report fromthe species
Synthesis of Homoisoflavonoids PART- B
We extended our work to synthesis of isolated homoisoflavonoids from Caesalpinia pulcerrima and of known homoisoflavonoids from Caesalpina sappan and Hoffmanosseggia intricate. These are related to flavonoids and occur as natural products and exhibit various biological properties.These compounds have been reported to possess antifugal,hyposholesterolemic,antimutagenic,antiviraland antioxidantactivities. Synthesis of these compounds is based on condensation of 4-chromanones with appropriate aromatic aldehydes in the presence of acidic or basic catalyst.
Retrosynthesis of some homoisoflavonoids is displayed below.
Scheme- 1
Accordingly we first prepared the 2′,4′-dihydroxy-3-chloropropiophenone 6 starting from commercial available resorcinol 5 by reaction with 3-chloropropionic acid 4 using trifluromethane sulphonic acid. We mainly focused on the synthesis of 7-hydroxychroman-4-one 7, a key intermediate in the synthesis of homoisoflavonoids. In the previous reports yields of this intermediate were less, reaction times were long and more number of steps were involved. To over come the problems, we prepared this intermediate through the reaction of resorcinol with 3-chloropropionic acid using trifluromethane sulphonic acid to afford 2′,4′-dihydroxy-3-chlosropropiophenone 6, which was cyclized using aqueous sodium hydroxide to give 7-hydroxy-4-chromanone 7 in high yields (63% for two steps) (Scheme- 2). Formation of the product was confirmed by its 1H NMR and mass spectra.
Scheme- 2
Scheme- 3
The piperdine catalyzed condensation of 7-hydroxy-4-chromanone 7 with 4-methoxy, 2,4-dimethoxy, 3,4-dihydroxy, 4-hydroxy, 3,4-methylenedioxy and 3-hydroxy-4-methoxy benzaldyhydes afforded 8 (bonducellin), 9 (2-methoxy bonducellin) 10,(sappanone A), 11, 12 and 13 in 68, 63, 58, 65, 60 and 69% yields respectively (Scheme- 3).
The condensation of 7-methoxy-4-chromanone 14, which was obtained from methylation of 7-hydroxy-4-chromanone 7 using iodomethane and K2CO3 with appropriate substituted benzyldehydes, 4-methoxy, 3,4-methylenedioxy and 3,4-dimethoxy benzaldehydes using piperdine gave compounds 15, 16 and 17 in 65%, 68% and 66% yields respectively (Scheme- 4). Formation of the products was confirmed by their 1H NMR and mass spectra.
Scheme- 4
Bonducellin 8 was photoisomerized to isobonducellin 18 using medium pressure mercury lamp in 48% (Scheme- 5). The spectral data (IR, NMR, and MS) of isobonducellin were identical with those of natural product. Bonducellin and 2′-methoxy bonducellin was converted into corresponding dihydrobonducellin 19 (95%) and dihyro-2′-methoxybonducellin 20 (92%) respectively using Pd/C hydrogenation in methanol (Scheme- 5). Formation of the products was confirmed by its 1H NMR and mass spectra.
Scheme- 5
The retro synthetic approach to the compounds intricatinol and intricatin are delineated in Scheme- 6.
Scheme- 6
The homoisoflavonoid, intricatinol (isolated from H. intricata) was synthesized from 7,8-dihydroxy-4-chromanone 28, a key intermediate obtained by the reaction of pyrogallol 26 with 3-chloropropionic acid 4 in the presence of trifluromethane sulphonic acid followed by cyclization with aqueous NaOH in 58% yield. Piperdine catalyzed condensation of 7,8-dihydroxy-4-chromanone 28with 4-methoxy benzaldehyde afforded intracatinol 29 in 63% yield.
Finally we attempted to synthesize the intricatin (isolated from H. intricata). The selective methylation of intricatinol 29 with dimethyl sulphate using NaHCO3 as a base gave intricatin 30 in 48% yield and dimethylated product 31 in 18% yields. The formation of the products was confirmed by their 1H NMR and mass spectra.
Scheme- 7
Another method for synthesis of intricatin involved 7-methoxy-8-hydroxy-4-chromanone 34, it can be obtained from the reaction of 3-methoxy catacohol 32 with 3-chloropropionic acid 4 using trifluoromethane sulphonic acid followed by cyclization with aqueous NaOH. 7-Methoxy-8-hydroxy-4-chromanone 34 and 4-methoxy benzaldehyde 23 condensed together in the presence of piperdine to afford intricatin 30 in 58% yields. Formation of the products was confirmed by its 1H NMR and mass spectra.
Scheme- 8
CHAPTER- II
Chemical Investigation on Orthosiphon glabratus and Synthesis of Chromene
and Chromenochalcone
Chemical Investigation on Orthosiphon glabratus PART- A
INTRODUCTION
Various species of Orthosiphon are known for their medicinal properties. The metabolites obtained from different species of Orthosiphon are also chemically interesting. These metabolites are of varied types, viz., different kinds of diterpenoids, monoterpene, polychiral furano pyrones, flavonoids, saponins and chromene compounds. The constituents of Orthosiphon species are thus both chemically and biologically interesting.
The present investigation relates to the isolation and characterization of twelve compounds from Orthosiphon glabratus which was not investigated earlier. These constituents belong to the chromenochalcones, chromenes, polychiral furano pyrones and flavonoids. The structures of the new molecules have been confirmed by its 1D and 2D NMR (1H-1H COSY, HMQC, HMBC and NOESY) and mass spectroscopic studies and by comparison with the structurally related compounds reported in the literature.
Table 2: Compounds isolated fromOrthosiphon glabratus
Compound code / Compound name / Compound nature /Remarks
OG-I / 1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3-(2,3,4-trimethoxyphenyl)-propenone / Light yellow amorphous powder /New compound
OG-II / 6-Acetyl-7-hydroxy-2,2-dimethyl chromene (eupatoriochromene ) / White crystals /First report from the species
OG-III / 3,5,7,4′-Tetramethoxy flavanoid / Colorless solid /First report from the species
OG-IV / 3,5-Dihydroxy-7,3′,4′-trimethoxy flavanoid (casticin) / Pale yellow solid /First report from the species
OG-V / OD-1 / Viscous mass /First report from the species
OG-VI / OD-VII / Viscous mass /First report from the species
OG-VII / 3,4-Dihydro-6-acetyl-(5-O-prenyl)-2,2-dimethylchromene / Colorless viscous /New compound
OG-VIII / 1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3-(4-methoxyphenyl)-propenone(pongachalcone-I) / Yellow solid /
First report from the species
OG-IX / 1-(5-Hydroxy-2,2-dimethyl-2H-chromen-6-yl)-3-(3-hydroxy-4-methoxyphenyl) -propenone (pongachalcone-II) / Yellow needles /First report from the species
OG-X / 8-Hydroxy-6,7-dimethoxy coumarine / Pale yellow solid /First report from the species
OG-XI / 3-Methoxy-4-hydroxy cinnamic acid (ferulic acid) / Colorless amorphous powder /First report from the species
OG-XII / 3-Hydroxy -4-methoxy cinnamic acid (Isoferulic acid) / Colorless solid /First report from the species
Synthesis of Chromene and Chromenochalones PART- B
We extended our work to syntheses of isolated chromenochalcones, chromenes, ferulic acid and isoferulic acid from Orthosiphon glabratusand of known chromenochalcones from Pongamia glabra and Loncocarpus utilus. These are related to flavanoids and occur as natural products and exhibit various biological activities These compounds have been reported to possess anticancer, antiinflammantory, antimitotic, antitubercular,cardiovascular, cell differentiation inducing nitric oxide regulation modulatory, antimalarial, antileishmanial, antihyperglycemic,antioxidant, antifeedant and antimicrobial activities. Synthesis of these compounds is based on condensation of acetylated chromenes with appropriate aromatic aldehydes in the presence of acidic or basic catalyst.
The retro synthetic approach to the chromenochalcones is delineated (Scheme- 9).
Scheme- 9
Accordingly we first prepared the 6-acetyl-5-hydroxy-2,2-dimethyl chromene36starting from commercial available resacetophenone with 3-methyl-2-butenal using pyridine. We are mainly focused on the synthesis of 6-acetyl-5-hydroxy-2,2-dimethyl chromene, a key intermediate in the synthesis of chromenochalcones (Scheme- 10). Because in the previous reports yields of this intermediate were less, reaction times were long and involves more number of steps. Along with 6-acetyl-5-hydroxy-2,2-dimethyl chromene 36 the minor product 6-acetyl-7-hydroxy-2,2-dimethyl chromene 37 was also obtained in 6% yield. The BF3.Et2O catalyzed condensation of 6-acetyl-5-hydroxy-2,2-dimethyl chromene with 4-methoxy, 3-hydroxy-4-methoxy, 3,4-methylenedioxy, 2-hydroxy-3-methoxy and 2,3,4-trihydroxy benzaldyhydes afforded 40, 41, 42, 43and 44 in 78, 83, 84, 81 and 83% yields respectively (Scheme- 11).
Scheme- 10
Scheme- 11
We have subjected the molecule 6-acetyl-5-hydroxy-2,2-dimethyl chromene 45 to catalytic hydrogenation in presence of 10% Pd/C catalyst in methanol to afford the desired 3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl chromene 46 in 93% yield (Scheme- 12).
O-prenyl-3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl chromene 47was obtained from prenylation of 3,4-dihydro-6-acetyl-5-hydroxy-2,2-dimethyl chromene 46 using prenylbromide and K2CO3 in acetone under reflux condition (Scheme- 12). The prenylation of 6-acetyl-5-hydroxy-2,2-dimethyl chromene also proceeded in similar conditions to form the corresponding O-prenyl product 45 (Scheme- 12).
Scheme- 12
The ferulic acid and its analogues are well-known as antioxidants and prevent oxidative damage of DNA by several mechanisms. In addition, these are also known to exhibit antiinfalammatory, antiprolferative, antiviral and immunoprotective properties. The ferulic acid and its esters are currently under development as a new drug candidate for the treatment of the dementia.
The retrosythetic approach is delineated in Scheme- 13.
Scheme- 13
We were also interested to synthesis ferulic acid and its regioisomer isolated from Orthosihon glabratus. We started the synthesis of ferulic acid (56) from commercially available 3-methoxy benzaldehyde 54, which was subjected to homologation by C-2 Wittig olefination using C-2 Wittig salt (Ph3P=CHCOOEt) in distilled benzene at reflux condition for 1.2 h to afford E and Z α, β-unsaturated esters 55a and 55b in combined yield of 98% (Scheme- 14). The trans isomer was found to be major (94%). Hydrolysis of ethyl ester 55a using 20% methanolic KOH under reflux for 2 h, followed by neutralization with aq. HCl afforded the desired ferulic acid 56 in excellent yield (91%) (Scheme- 14).
Scheme- 14
The synthesis of isoferlic acid 59 was started from commercially available 4-methoxy-3-hydroxy benzaldehyde 57, which was subjected to homologation by C-2 Wittig olefination using C-2 Wittig salt (Ph3P=CHCOOEt) in distilled benzene at reflux condition for 1.2 h to afford E and Zα, β-unsaturated ester 58a and 58b in combined yield of 98% (Scheme- 15). The trans isomer was found to be major (94%). Hydrolysis of 58a using 20% methanolic KOH under reflux for 2 h, followed by neutralization with aq. HCl afford the desired ferulic acid59 in excellent yield (93%) (Scheme- 15).
Scheme- 15
CHAPTER- III
Development of New Synthetic Methodologies for Formation of Heterocyclic Compounds
Heterogeneous catalysts-an overview PART- A
In the 20th century, a seemingly very different type of catalysis, heterogeneous catalysis, became the foundation for much of the chemical industry. It plays a central role in generating the feed stocks for making the synthetic materials that we use every day, from fuels to fertilizers. New experimental techniques have brought fresh insights into this form of catalysis, and it now seems that there are more similarities between enzymes and heterogeneous catalysts than initially meets the eye.
An extensive application of heterogeneous catalysis in synthetic chemistry can help to achieve new selective reactions, to lower the waste production, and, finally, to render more attractive the synthetic process from both the environmental and also the economic point of view, in agreement with some parameters of the “ideal synthesis”.
Generally the classical synthetic methodologies involve expensive reagents and catalysts, which are not easily available and require harsh reaction conditions. Thus there is a need to replace such reagents and catalysts. Recently there is also a much greater demand on organic chemists for innovation of new mild synthetic methodologies in view of the stipulations laid down by the environmental systems. The threat to ecological and environmental synthesis due to the damages caused by the chemicals has put forward a new area of the so called “Green Chemistry”.
PRESENT WORK PART- B
3.0 Development of New Synthetic Methodologies
Different improved processes are now being discovered to carry out the reactions efficiently and conveniently with readily available inexpensive materials. During the present study utilizing heterogeneous as well as homogeneous catalysts some important synthetic methodologies have been developed for synthesis of heterocyclic compounds.
3.1. An efficient synthesis of 1,8-dioxo-octahydroxanthenes using heterogeneous catalysts
Xanthenes and benzoxanthenes have received much attention because of their wide range of therapeutic and biological properties, such as antibacterial, antiviral, and anti-inflammatory activities. Furthermore, these compounds have emerged as sensitizers in photodynamic therapy and are used as leuco-dyesand in laser technology.
Heterogeneouscatalysts have gained interesting attraction in recent years due to economic and environmental considerations. These catalysts are generally inexpensive and easily available. They can conveniently be handled and removed from the reaction mixture, thus making the experimental procedure simple and eco-friendly.
We have observed that 5,5-dimethyl-1,3-cyclohaxanedione 60 can easily undergo the condensation with aromatic aldehydes 61 in the presence of silica supported sodium hydrogen sulfate (NaHSO4.SiO2) or silica chloride to from 1,8-dioxo-octahydroxanthene derivative 62 (Scheme- 16). The mixture of 60 and 61 was refluxed in CH3CN using either of these two catalysts.Earlier, compound 62 was not synthesized using a heterogeneous catalyst.
Scheme- 16
15 Examples
We have developed a convenient and efficient method for the synthesis of 1,8-dioxo-octahydroxanthenes utilizing two heterogeneous catalysts, NaHSO4.SiO2 and silica chloride. The simple experimental work-up, high yields and applications of inexpensive catalysts are the advantages of the present procedure.
3.2: Amberlyst-15: An efficient reusable heterogeneous catalyst for the synthesis of 1,8-dioxo-octahydroxanthenes and 1,8-dioxodecahydroacridines
Acridine derivatives containing the 1,4-dihydropyridine unit belong to a special class of compounds, not only because of their interesting chemical and physical properties but also owing to their immense utility in the pharmaceutical and dye industries; they are also well-known therapeutic agents.
Here we have observed that Amberlyst-15 is an efficient heterogeneous catalyst for the synthesis of 1,8-dioxo-octahydroxanthenes 62 and 1,8-dioxo-decahydroacridines 63. The former were prepared from a mixture of 5,5-dimethyl-1,3-cyclohexanedione 60 and aromatic aldehydes 61 by heating in CH3CN under reflux in the presence of the catalyst while the latter from this mixture along with amines under the similar reaction conditions (Scheme- 17).
Scheme- 17
15 Examples
We have developed a novel and efficient method for the synthesis of 1,8-dioxo-octahydroxanthenes and 1,8-dioxo-decahydroacridines in high yields employing Amberlyst-15 as a heterogeneous solid acid. The application of an inexpensive, easily available and reusable catalyst makes this method simple, clean, practical and economically viable. The method is an easy access to functionalized xanthenes and acridines.
3.3. Efficient synthesis of 3-alkyl indoles through regioselective ring opening of epoxides catalyzed by sulfated zirconia
Indole derivatives are key structural motifs in many pharmacologically and biologically active compoundsand as well as in many natural products.3-Alkylindoles have significant medicinal importance and they can be prepared by Friedel- Crafts alkylation of indoles using epoxides.
During the development of useful synthetic methodologies we observed that the styrene epoxide 64 can be opened smoothly with indole 65 in the presence of sulfated zirconia in CH2Cl2 to afford the corresponding 3-alkylindoles 66 at room temperature (Scheme- 18).
Scheme- 18
15 Examples
Sulfated zirconia has been used here for the first time as an efficient catalyst for the preparation of alkylated nitrogen heterocycles at room temperature from various epoxides and nitrogen heterocycles. The mildness of the conversion, simple experimental procedure, impressive regioselectivity and reusability of the catalyst are the notable advantages of the present method.
3.4. Selective acetylation of alcohols, phenols and amines and selective deprotection of aromatic acetates using silica supported phosphomolybdic acid
Protection of functional groups is highly essential in organic synthesis. The alcohols, phenols and amines are frequently protected as acetates, which are generally prepared by reaction with Ac2O in the presence of pyridine. (Dimethylamino) pyridine (DMAP) and 4-pyrrolidino pyridine (PPY) are also known to catalyze the acetylation of alcohols.
We have observed that silica supported phosphomolybdic acidis very suitable to catalyze the acetylation of alcohols and phenols with acetic anhydride to form the corresponding acetates at room temperature (Scheme- 19). The chemo selectivity of the present acetylation method is remarkable. An alcoholic hydroxyl group can conveniently be acetylated keeping intact the phenolic hydroxyl group in a molecule.
Scheme- 19
31 Examples
Phenolic hydroxy groups are present in several bioactive naturally occurring compounds. Hence protection and subsequent deprotection of this group is necessary for multistep transformations and synthesis of these compounds. We have observed that silica supported phosphomolybdic acid is a highly efficient catalyst for chemoselective deprotection of aromatic acetates in methanol at room temperature within 2-3 h. Several aromatic acetates underwent deprotection in the presence of the catalyst to produce the corresponding parent phenols (Scheme- 20).
Scheme- 20